The development of vascular grafts and medical devices that contact physiological fluids, particularly blood, is a rapidly developing area of medicine. This has been hampered, however, by the lack of suitable synthetic materials that are stable when contacted with such fluids.
Adverse reactions between materials and blood components are predominant factors limiting the use of synthetic materials that come into contact with physiological fluids. For example, catheters, vascular grafts, and the like, tend to serve as a nidus, or focus, for the formation of thrombi (blood clots). Initial contact of such materials with blood results in deposition of plasma proteins, such as albumin, fibrinogen, immunoglobulin, coagulation factors, and complement components. The adsorption of fibrinogen onto the surface of the material causes platelet adhesion, activation, and aggregation. Other cell adhesive proteins, such as fibronectin, vitronectin, and von Willebrand factor (vWF) also promote platelet adhesion. As a result, the continual use of anticoagulants in conjunction with the introduction of such materials to the body is often necessary.
Furthermore, complement activation occurs when materials are introduced into blood. Adsorption of large amounts of IgG, IgM, and C3b onto surfaces causes activation. Subsequently, complexes may be formed which contribute to undesirable immune responses, such as proteolysis, cell lysis, opsonization, anaphylaxis, and chemotaxis. As a result, these responses render such materials incompatible with the living body.
A number of approaches have been suggested to improve the biocompatibility, and even blood compatibility, of medical devices. Heparinization of polymers is one such approach. In one method, heparin is complexed with a quaternary amine prior to coating the complex onto a polymeric surface. Heparin can also be immobilized onto segmented polyurethane-urea surfaces using hydrophilic poly(ethylene oxide) spacers of different chain lengths, as disclosed in K.D. Park et al., J. Biomed. Mater. Res., 22, 977-992 (1988).
Another heparinization method, which is disclosed in U.S. Pat. No. 5,229,172 (Cahalan et al.), involves initially irradiating a polymeric surface in the presence of an oxygen source and then grafting acrylamide to the irradiated surface using an acrylamide monomer and ceric ions. The grafted acrylamide surface, which can optionally be modified to include pendant functional groups such as amine and carboxyl groups, provides a suitable surface to which a biomolecule can be ionically or covalently bonded. For example, the graft can be subjected to hydrolysis in order to introduce carboxyl groups, to which spacer molecules like ethylenediamine can be coupled, using carbodiimide. To the aminated graft biomolecules such as heparin can be bound using a coupling agnet such as carbodiimide.
Thus, many of the methods of attaching biomolecules, particularly heparin, to surfaces involve multiple steps. In addition to the steps discussed above, the biomolecule may initially be modified to include reactive functional groups. For example, heparin is often oxidized by a periodate to form aldehyde functional groups.
Thus, a need exists for more efficient methods for attaching biomolecules, particularly heparin, to surfaces, particularly those that form a part of a medical device.